Put the words "cancer," "chemotherapy" or "radiation" in
front of anyone in the
public, and these are the phrases you are likely to hear
in response.

Sure, all drugs carry the risk of side effects,
but oncology
therapeutics hold a special place in people's psyches. At the same time, when
presented with the diagnosis of cancer, few patients are
going to say, "thanks,
but no thanks."

Side effects are the new normal when it comes to having your
cancer
treated—part of the risk-benefit equation—and it is accepted.

Cost of doing
business?

Even in clinical circles, there has become a certain
expectation when treating patients with
oncology therapeutics. When presented
with a new therapeutic on the market, oncologists can look at a safety profile
that includes 75 percent of
patients experiencing some degree of neutropenia
(for example), and respond that this is within normal parameters for other
drugs in the same category
and/or for the same condition.

The clinicians aren't necessarily blasé about the side
effects. They simply don't feel like there are any
alternatives out there.

Unfortunately, this belief itself can have a cost when a new
drug enters even the research phase.

One of the major side effects associated with
immuotherapeutics targeting the EGFR tyrosine kinase (e.g., gefitinib
and erlotinib) is a significant, if not necessarily
debilitating, rash. And despite a lack of supporting evidence—at least
initially—many oncologists
believed the rash was a sign that the drug was
working, and sold the benefit to patients.

Over the last handful of
years, further studies on these two
drugs have shown that patients with non-small-cell lung cancer (NSCLC) who
experience the rash do seem to perform
better in treatment, so there may have
been some merit to this belief.

But then came the introduction of another member of this
family, nimotuzumab, an anti-EGFR for which rash was not a significant side
effect. Anecdotally, while the absence of rash might have been hailed as a
step
forward, it met with resistance. Without the rash, some clinicians found it
hard to believe that the drug was actually providing benefit, despite
clinical
evidence in conditions such as glioma.

The expectation of side effects has become so deeply
ingrained in this category that the absence of a key side effect was grounds
for disbelief by some.

The development of new drugs has typically
focused on
efficacy first (benefits), safety second (risks). But as was discussed last
month (see "Good enough is no longer good enough,"ddn March 2013), efforts to raise the efficacy bar have become more
difficult in
recent years.

So, if the industry can't necessarily raise the benefits
side of the equation, can it lower the
risks side? Do side effects have to be
the new normal? Or is there a way to either prevent or better ameliorate some
side effects?

Easy dose it

Some companies have refused to give up
completely on the
efficacy side of the equation, believing there is still room to improve
therapeutic efficacy without necessarily increasing side
effects. For Lawson
Macartney, CEO of La Jolla, Calif.-based Ambrx,
it's about finding the right
balance between the two sides, and his company is betting on improving
therapeutic potency.

Often when cancer patients experience debilitating or
life-threatening side effects, their oncologists will either reduce
their dose
or stop therapy—"a treatment vacation"—until they can recover. Ambrx is taking
a similar approach in the development of its therapeutics,
but rather than wait
for something to go wrong before lowering a drug dose, the company wants to use
minimal dosing ahead of time by making its drugs
that much more specific and
potent.

"The old cancer medicines were notoriously non-specific,"
Macartney
explains. "They've been basically toxins and have had horrible side
effects. Modern agents are much more targeted, which means that you can give
less
of it. Unfortunately, in the old days, not until you were able to show
efficacy and safety were you then able to move molecules like Herceptin or
Tykerb upstream in the treatment paradigm, to say, adjunctive therapy or in
chemo-naïve patients."

Macartney
sees antibody-drug conjugates (ADCs) as the next
step in this evolution, smart bombs that use tumor-directed antibodies to
deliver a chemotherapeutic
payload, the two held together with a chemical
linker.

ADCs are not new. What is new is the
specificity with which
they are constructed.

"In traditional molecules that are currently available,
the
linker attaches at several different sites on the antibody, which on the plus
side means that you potentially get lots of therapy molecules,"
Macartney says.
"On the down side, however, you may get none or you may get so many that it
actually interferes with the antibody binding."

You end up with a really heterogeneous population of
molecules that can be difficult to characterize and may interfere
with specificity
and potency.

Rather than rely on the native amino acids for chemical
linkage, Ambrx engineers the antibody with a specific non-natural amino acid
located optimally for greatest therapeutic potency.

"The goal is to decrease the dosage necessary for efficacy,
increase the relative efficacy and by doing this,
improve the therapeutic
window between where we start to see efficacy and where we start to see side
effects," adds Macartney.

Perhaps the poster-child for ADCs currently is Seattle
Genetics' Adcetris (brentuximab vedotin), which has been FDA-approved for
Hodgkin lymphoma and systemic ALCL, but is actively
being tested in a variety
of other cancers.

Several other companies are following closely
behind,
however, including the Phase III programs of Genentech/Roche's trastuzumab
emtansine ADC against HER2+ metastatic breast cancer and Pfizer's inotuzumab
ozogamicin ADC against relapsed/refractory acute lymphoblastic leukemia (ALL)
and relapsed/refractory non-Hodgkin lymphoma.

The true test of Ambrx's lead oncology
product,αHER2-ADC, is still to come as it is
in preclinical phases, but the company is in active discussions with several
pharmaceutical companies
to bring it into the clinical domain.

As Macartney
explains, to increase the likelihood of success and proof of
concept, the
obvious first target is breast cancer, but as HER2 is expressed in a number of
other tissues, other cancers are viable targets
downstream.

Looking for trouble

The
ultimate goal, of course, would be to build a
therapeutic product that only hit its intended target and offered few side
effects from off-target
interactions or its own intrinsic toxicity.

Over the last decade or so, computational scientists and
informatics companies like ACD/Labs and Simulations Plus have tried to find ways
of predicting potential side effects, at least at the small molecule level, by
performing comparative analyses of known and experimental molecules, using
techniques such as quantitative structure-activity relationship (QSAR),
with
varying degrees of success.

One potential reason for the variable success of many of
these methods for identifying off-target effects by
drugs may be the
inadvertent separation of a therapeutic's molecular identity and its
pharmacological effects.

"In the modern era of molecular biology, we can look at the
structures and sequences of protein targets, and perhaps say, I know this is
a
serotonin type 1 receptor, I know what it looks like and I can see what drugs
bind to it," says Michael Keiser, founder and chief operating officer
of
SeaChange Pharmaceuticals. "Because of that ability,
however, we've kind of
forgotten how to organize therapeutics by their pharmacological effect. So you
might look at the highly related targets for a
particular drug, but you might
not think to look for a different sort of target."

"On the one side, we have a single
drug, and on the other
side, we have all of the known ligands for a single target, and we compare
those two-dimensional structures in a statistical
way," he says. "If we do the
comparison right, then the shape of the probability distribution is what's
called an extreme value distribution."

Their similarity ensemble approach (SEA) allows SeaChange to
link potential drugs to an entire panel of molecular
targets and predict
whether the drug might interact with one or some of those targets. Once they
have the target profile, they then ask out of those
target profiles, which targets
are associated with particular side effects.

As presented in Nature
in
last year, the group tested SEA on a panel of 656 prescribed drugs
against 73 known targets and identified 1241 potential side effect targets, of
which
348 were known in NIBR's proprietary data. A further 151 side effects,
previously unidentified, were later confirmed through lab testing at NIBR.

Said UCSF professor Brian Shoichet when the results were
announced, "The biggest surprise was just how promiscuous the drugs were, with
each
drug hitting more than 10 percent of the targets, and how often the side
effect targets were unrelated to the previously known targets of the drugs.
That would have been hard to predict using standard scientific approaches."

The group examined the chemical substructures and known side
effects of almost 1,000 drugs to identify statistical links between the
two,
and then used this information to identify potential side effects for compounds
that did not have side-effect data. In one example, they noted a
link between
the anti-obesity compound rimonabant and key phrases such as "borderline personality
disorder" and "PTSD."

In 2008, rimonabant was pulled from the European market
for side effects that included severe depression.

Both
Stoven and Keiser see strong utility for their methods
early in the drug discovery process.

"A toxicologist has a
hard position, because more often than
not, you don't get to evaluate or even see any of the compounds until they're
quite a ways along," Keiser
says. In other words, a point at which many choices
have been made and you're faced with a decision to kill a program: "One of the
reasons for this
is that the assays needed to make sure there are no negative
effects are expensive," Keiser notes.

"Computationally, instead of only being able to evaluate
four compounds, you can contribute earlier on when you are still looking at a
thousand
candidates, and differentiate them not just on efficacy but also on
potential off-targets," he adds. "You aren't replacing safety assays, but you
are highlighting what products to test."

But even if you could limit the potential side effects
of
drugs coming down the discovery and development pipeline, those drugs won't
likely hit the market for another decade. What can we do for patients
now?

Shielding patients

With the advent of
personalized medicine came the
opportunity to identify what patients would most likely benefit from what
drugs. But even here, with all of the
diagnostic tools at our disposal and an
expanding arsenal of targeted therapeutics, the focus has been on the cancer,
rather than the patient.

"Everyone is looking at the genomics of tumors, and they're
trying to develop therapies based on that," says Ed
Rubenstein, president and
CEO of InformGenomics.
"One fundamental problem with this approach is that
cancer by its nature is a fundamental instability of DNA, so what people may be
looking at is the
consequence, rather than the cause of cancer."

Furthermore, he stresses, cancer is constantly evolving,
responding to Darwinian pressures. When you expose a heterogeneous population
of malignant cells to chemotherapy, you kill off the easy ones. The more
unstable, harder-to-treat ones continue to evolve.

InformGenomics looks at the problem from
another
perspective.

"A patient's inherent DNA is relatively stable, aside from
epigenetic changes, but
there are probably genetic bases for every side
effect," Rubenstein explains. "And there is lots of evidence to support that
the biologic pathways
responsible for these side effects are under genetic
control."

Thus, like SeaChange Pharmaceuticals and the group
at Mines
ParisTech, InformGenomics is applying biological networks with its OnPart
platform, but in its case, to side-effect pathology and risks,
rather than
small-molecule characterization.

Rubenstein is quick to point out, however, that this is
not
the typical biomarker diagnostics effort typically associated with personalized
medicine (see "A companion in your corner,"ddn
October 2012).

"Genes work together in
networks," he says. "If you look at
most of the predictive biomarkers or genetic markers, they're not
network-based, they're standard-frequency
statistically based. Genes talk to
each other, there's lots of biologic feedback and interaction, so we are using
advanced Bayesian networks to
discover those genes that interact with one
another. The way we're doing that is using SNPs as markers."

By
linking patterns of SNPs to various biological networks,
the company found it could create individual networks for individual side
effects. Thus,
Rubenstein explains, the nausea-vomiting networks had
neurotransmitter and neurosignaling terms, which said they were on the right
track. Similarly,
some of the genes that were mapped by the diarrhea network
have been implicated in other inflammatory diarrhea pathologies like Crohn's
disease and
ulcerative colitis.

For InformGenomics, however, it is not just about
statistics. It is also
very much about the patient and his or her desires,
concerns and fears.

Thus, a key component of OnPart is a validated
patient
questionnaire—the Preference Assessment Inventory—that quantifies the patient's
attitudes about potential side effects.

"It empowers patients because not only does OnPart determine
their own genomic risks, but it also captures how they view
those side effects,
how important they are to them in their day-to-day life," Rubenstein explains,
giving the example of a concert pianist or computer
coder whose biggest fear is
peripheral neuropathy. "That information goes back to the oncologist so they
can have that real informed-consent
discussion about the risks and benefits of
chemotherapy options."

At the ASCO Gastrointestinal Cancers Symposium
in January,
InformGenomics presented the findings of a study of OnPart in 384 patients who
received the modified FOLFOX regimen +/- bevacizumab for a
variety of cancers
to see how accurately the platform could predict a set of side effects. Their
predictive networks had accuracies beyond 90 percent.

In announcing the findings, Lee Schwartzberg, lead
investigator and Medical Director of The West Clinic, said,
"This allows us to
customize our chemotherapy regimens and side effect control interventions for
best patient care. These side effects can impair
function, create inefficiencies
in medical practice and are costly to patients and payers."

InformGenomics is
also developing a similar system for
patients receiving stem cell transplants. According to Rubenstein, about 40 percent of patients
receiving high-
dose chemotherapy and stem cell transplant will develop serious
oral mucositis, meaning lesions of the mouth, serious infection, prolonged
hospitalization and an increased risk of mortality, but it is impossible to
predict which patients using clinical factors.

"Prophylactic drugs are available to prevent the oral
mucositis, but they are very expensive, and if only four out
of 10 patients are
going to benefit, it is hard to justify the use of that agent," he says. "If we
can predict who is going to get serious oral
mucositis, then it allows an
already approved drug to be targeted appropriately to the patients who are going
to benefit. We see that as another way to
take cost out of the system."

So where are we with those prophylactic treatments?

Making things better?

As founding chair of the NCCN Febrile Neutrogena Panel,
member of the NCCN Antiemetic Guidelines
Panel and member of the MASCC board of
directors, Rubenstein is
well positioned to understand the armamentarium of
side effect treatments.

In the earliest days
of oncology, drug toxicity essentially
forced oncologists to develop supportive care as patients were almost as likely
to die from their treatments as
from their cancer, he explains.

"That led to
the advent of prophylactic antibiotic therapy for neutropenic fever and
the
development of pheresis machines and blood component therapy."

"The second wave of cancer supportive therapy
was the
development of effective antiemetics, which was usually a combination of things
that had lots of side effects, but then the 5-HT3 receptor
antagonists were
developed," he adds. "Around the same time, you got better advances in antibiotics
and then the development of blood cell growth
factors."

Those advances continue. As mentioned earlier, oral
mucositis can be an incredibly
debilitating side effect of many chemo and
radiation therapies, afflicting almost 500,000 cancer patients each year in the
United States alone. At
present, there are few therapeutic options available to
patients other than pain management, Access Pharmaceuticals' MuGard being a
major player.

Last summer, at the MASCC conference, Access presented
Phase IV studies of MuGard in patients undergoing chemoradiation therapy for
head-and-
neck cancer, showing significant reduction in mouth and throat
soreness and delay in mucositis onset, as well as reductions in weight loss and
use of
opioid medications.

Less advanced in development is the defensin mimetic
brilacidin from PolyMedix, which is just entering Phase I trials. Part of a new
class of
antibiotics, brilacidin has shown antibacterial, antibiofilm and
anti-inflammatory activity in various animal models, leading to an NCI grant
last
September for the Phase I study the company hopes to initiate this year.

Slightly ahead of brilacidin is Soligenix's oral mucositis
candidate SGX942, a fully synthetic pentand
radiation therapy. The company
describes the product as an innate defense regulator that stimulates the innate
immune response to damage. In
preparation for its Phase II study, which the
company expects to initiate in the second half of 2013, Soligenix announced the
formation of a mucositis
medical advisory board in February.

As Rubenstein suggests, great strides were made in the
treatment of
chemotherapy-induced nausea and vomiting (CINV) with the advent of
the 5-HT3 receptor antagonists, the most recent entrant being Eisai's Aloxi
(palonosetron), but even here, companies continue to seek improvements.

For example, last September, A.P. Pharma resubmitted its NDA
to the FDA for its lead product, APF530. Essentially the 5-HT3 receptor
antagonist granisetron, APF530 has been
formulated for a more durable response
on a single injection. The hope is to extend granisetron's current indication
for acute-onset CINV (first
treatment day) to include delayed-onset CINV (up to
five days), putting it more on par with Aloxi, which is indicated for both
acute and delayed
onset.

OPKO Health,
meanwhile, in partnership with Tesaro, is
currently in Phase III
trials with its CINV candidate rolapitant, a
neurokinin-1 receptor antagonist that it is testing in three studies of
patients receiving highly- and
moderately-emetogenic chemotherapy with standard
of care, which includes a 5-HT3 receptor antagonist and the steroid
dexamethasone. The company expects
the results of the trials for late 2013.

And of course, several companies continue to push various
marketed
supportive care products through clinical trials, looking for expanded
applications. Such is the case with Amgen, which continues to test Neulasta
(pegfilgastrin) against febrile neutropenia. In
January, the company announced
the results of its Phase III PAVES trial in metastatic colorectal cancer,
showing significant reduction in the incidence
of grade 3/4 febrile neutropenia
versus placebo.

Alder Biopharmaceuticals took a step back, however, and
decided there had to be something better than the current
whack-a-mole approach
to tackling side effects; that is, hitting them as they arise, or are expected
to arise. The company took a more holistic
approach by looking for
commonalities in the root causes of many side effects.

Alder focused on the pathways controlling inflammation, and
specifically on the cytokine interleukin-6 (IL-6).

"There's a number of places where inflammation plays a role
in a negative sense for cancer patients," explains Randall Schatzman, company
president and CEO. "First and foremost, the cancers themselves release
pro-inflammatory molecules like IL-6, which cause a lot of inflammation
secondary to the tumor. And this inflammation is really responsible for a
large
percentage of the morbidity and mortality."

The second place inflammation plays a role is in
tumorigenesis
itself and how certain chemotherapies work on the tumor, such as in the
development of resistance. And finally the problems that
chemotherapy itself
causes—e.g., anemia and oral
mucositis—side effects of chemotherapy that Alder believes are driven by
pro-inflammatory
cytokines.

"What we're trying to do is tease out the role of
inflammation within this remit of paraneoplastic
issues and chemotherapy side
effects, because at the end of the day, oncologists want to get as many cycles
of chemotherapy into a patient as possible
to increase their chances of getting
a complete response," adds Jeffrey Smith, Alder's senior vice president of
translational medicine. "If the
patient is saying time out after, say, three
cycles out of six because of the side effects, then clearly, the oncologist
isn't winning. It's a
suboptimal treatment of the patient's cancer."

As Smith sees it, it's about more than simply
controlling
side effects to improve patients' quality of life, and therefore making
treatment easier. It's also about getting more cycles into the
patient to
improve the chances of killing the cancer off. It's about both efficacy and
safety.

Alder's lead cancer product, ALD518, currently in several
Phase II studies, is a humanized anti-IL-6 monoclonal antibody that keeps the
cytokine from interacting with its receptor and triggering a variety of
cancer-related conditions such as catexia (wasting), anemia, oral mucositis and
acute graft-versus-host disease.

Smith sees opportunities for ALD518 not only in preventing
some of the side effects of chemotherapy, but also in helping to modulate the
body's response to immunostimulatory regimens, using the recent case of
children being treated for ALL as almost a proof of concept.

In that study, patients received modified
T-cells designed
to attack the leukemia, but in some cases, the patient's immune system was
overstimulated and the therapy triggered a cytokine storm
that threatened to
kill the patient. When one oncologist noted that a patient's IL-6 levels had
spiked, he prescribed her Actemra (tocilizumab), an
antibody used in rheumatoid
arthritis that targets the IL-6 receptor. Within hours, the patient stabilized.

Smith
thinks a day is approaching when this type of regimen
becomes the paradigm, not the anecdote.

"I could
foresee more of that, where agents such as an
anti-TNF or anti-IL-6 or other agents that modify the immune system are used to
damper down unwanted
effects of immunostimulatory regimens," he says.

Schatzman also sees the holistic approach as
paying off from
a payor perspective.

"It's one thing to have an agent that makes patients
feel
better, and it's another to have an agent that improves outcomes," he says. "I
think the burden is on us to do the latter because when you
improve clinical
outcomes rather than just patient-reported outcomes, payors are more willing to
pay."

And at the end of the day, as with any industry, it's about
getting paid.